Huntington's disease (HD) is an autosomal dominant neurological amyloidogenic disease. 5 to 10 individuals per 100,000 individuals are affected with this autosomal disease. However, the prevalence in the US is much higher, studies have shown that under 200,000 US individuals 50% have the risk of developing HD, in particular 30,000 patients are registered in the US while only 100,000 patients are registered worldwide.
HD, as shown in several studies, results from a trinucleotide CAG repeat expansion in the Huntingtin (HTT) gene, in particular in exon 1 of the HTT gene located on chromosome 4 (MacDonald et al., Cell 72, (1993), 971-983), which is translated into a polyglutamine (polyQ) stretch in the HTT protein. HD occurs when the polyQ tract exceeds a threshold of 35-40 glutamine residues in length with a strong inverse correlation between repeat length and age-of-onset of disease. This polyQ stretch leads to a misfolding and aggregation of HTT in several regions, e.g. neurons and glial cells. With increasing age an accumulation of the HTT aggregates takes place leading to degeneration of the striatal GABA-ergic neurons and cortical pyramidal neurons. Symptoms of the HTT misfolding and aggregation include involuntary movements, lack of motor coordination, depression, cognitive decline such as memory loss and/or dementia.
Since 1993 when the HD mutation was identified the understanding of the pathophysiology and molecular biology of the disease has significantly improved. Medicaments such as e.g. Xenazine® (tetrabenazine, Lundbeck) a hexahydro-dimethoxy-benzoquinolizine derivative VMAT2 inhibitor had been designed for symptomatic treatment targeting involuntary muscle movements.
In addition, gene silencing approaches such as RNA interference (RNAi) have been suggested as potential therapies. In particular, the use of siRNA directed against HTT gene in a HD mouse model (R6/2) was shown to inhibit mutant HTT gene expression, see e.g. Warby et al., Am. J. Hum Genet. 84 (2009), 351-366 and Olshina et al., Biological Chemistry 285 (2010), 21807-21816. However, one limitation of this method lies in the difficulty to introduce sufficient amount of siRNA into the target cells or tissues as shown by e.g. Boudreau et al. (Brain Research 1338 (2010), 112-121). Furthermore this approach may face safety liabilities as a continued need for the expression of Huntingtin was suggested by gene deletions studies in animal models and cultured cells (Dragatsis et al., Nat. Genet. 26 (2000), 300-306; Gauthier et al., Cell. 118 (2004), 127-138; Zuccato et al., Nat. Genet. 35 (2003), 76-83).
Therefore, there is a need for novel therapeutic strategies an efficacious and safe therapy of diseases associated with HTT aggregation which preferably directly interfere with amyloid formation by mutant HTT.
This technical problem is solved by the embodiments characterized in the claims and described further below and illustrated in the Examples and Figures.